Focus
Authors: Didier Samuel
Journal: Journal of Hepatology (2009)

The addition of ribavirin (RBV) to interferon-based therapy against hepatitis C virus (HCV) has been a therapeutic breakthrough. All therapies against HCV are based on a combination of pegylated interferon and RBV. The mechanism(s) of action of RBV remain partly unknown. The first attempts at triple drug therapies with protease inhibitors plus interferon showed that addition of RBV remains an essential element to achieve sustained virologic response (SVR). However, intake of RBV is associated with a severe dose-dependant haemolytic anaemia limiting the tolerance and the efficacy of treatment. Viramidin (VRD) is a prodrug of RBV and is metabolized primarily in the liver to RBV without accumulation of VRD in red blood cells thus reducing the degree of anaemia with an expected similar antiviral effect. In a phase III study described by Marcellin et al., a combination of VRD 600 mg bid plus Peginterferon alpha 2a was compared to a standard dosing regimen of RBV plus Peginterferon alpha 2a. Overall, SVR was higher in the RBV group (54%) vs. the VRD (40%) group and the non-inferiority point, a main objective of the study, was not reached. This trend of lower SVR in the VRD group was confirmed in genotypes 1 and 2/3 HCV patients. As expected, there was significantly less decrease in haemoglobin (54%) in the VRD group than in the RBV group (80%) p< 0.001. The lower efficacy of VRD in comparison to RBV still remains a debateable issue. The authors suggest that the optimal dosages of VRD still remains to be established; therefore, further studies are required to test the hypothesis that different dosages of VRD will provide a better safety profile with a similar efficacy as compared to RBV. The standard of care for HCV infected genotype 1 patients is the combination of Peginterferon recombinant alpha plus ribavirin for a duration of 48 weeks. There is a debate on the duration of therapy in those patients who achieve a rapid decline in viral load (>2 log drop at week 4) or a complete suppression of viral load (i.e. HCV RNA <50 IU/ml) at week 4. Some reports have suggested that in these patients a shorter treatment duration of 24 weeks would achieve a similar SVR with improved tolerance at a lower cost. However, higher relapse rates have also been reported in such patients. In a meta-analysis of 7 randomized controlled trials, Moreno et al., in this issue looked at the impact of shorter treatment duration on the SVR rate in HCV genotype 1 patients. Overall the SVR rate was lower in the short duration treatment groups due to a higher virologic relapse rate. In the subgroup of patients with RVR at week 4 and with a HCV RNA pre-treatment level below 400.000 IU/ml, the SVR rate was similar in both groups. Thus, the advantage of a shorter duration of therapy in genotype 1 patients seems limited to a small group of patients with rapid virological response and low viral load. Sorafenib has recently been licensed for treatment of unresectable hepatocellular carcinoma (HCC). Sorafenib targets Raf, Vascular endothelium growth factor receptor 1, 2, and 3 (VEGF-Rs) and platelet derived growth factor receptor (PDGF-Rβ). Sorafenib has been shown to improve survival in comparison to conventional treatment in patients with advanced unresectable HCC. The exact mode of action of Sorafenib is still unknown; however, its main action is believed to be through inhibition of VEGF-R. Despite the important therapeutic advance provided by Sorafenib, there is still a long way to go in control of HCC. Two studies in this issue of the Journal have explored the potential of enhanced activity of Sorafenib in combination therapy with other drugs. Chen et al. looked at the mechanism of the synergistic interactions between Sorafenib and bortezomib. Bortezomib is a proteasome inhibitor approved for the treatment of multiple myeloma. HCC cells in culture such as PLC-5 are highly resistant to bortezomib-induced apoptosis due to the inability of bortezomib to down regulate phospho-Akt in these cells. The investigators showed that pre-treatment with Sorafenib overcomes resistance to bortezomib in PLC-5 HCC cells and this effect is mediated through protein-phosphatase 2A (PP2A)-Akt inactivation. The Raf/MEK/ERK pathway is an important pathway in liver tumorigenesis. Huynh et al. showed that the inhibition of MEK/ERK pathway by AZD 6244 enhanced the antitumor effect of Sorafenib in a mice model of HCC. This paper suggests that a combination of angiogenesis inhibitors and the ERK/MEK pathway are effective to suppress tumour growth in a xenograft model of HCC by suppressing the feedback activation pathway of ERK/MEK. Thus, the anti-tumoral effect of the combination of Sorafenib/AZ 6244 was more effective than Sorafenib monotherapy in this model. In a third paper, Aihara et al. described the effect of AZD1152, an Aurora B kinase inhibitor on HCC growth. The Aurora kinase family of serine–threonine kinases controls chromosome assembly and segregation during mitosis. Aberrant expression of the Aurora kinases has been reported in several solid tumours. The effect of AZD1152 has been tested in human HCC cell lines and in a heterotopic and orthotopic xenograft mouse model. In these models, AZD1152 decreases tumour volume and improves survival of treated mice. Thus, the fundamental research in controlling HCC pathways is expected to open the field for new therapies against HCC; however, these experimental results require confirmation in human HCC patients.